Research Article

iMedPub Journals 2021

Journal of Veterinary Medicine & Surgery
http://journals.imedpub.com ISSN 2574-2868 Vol. 5 No. 1: 31

Retrospective Case Control Study of Pet Benjamin Lamglait1,

Andreas Brieger2,3, Marie
Ferrets with Cystine Urolithiasis in Quebec, Pierre Rainville4, Edouard
Canada: Epidemiological and Clinical Features Maccolini1,5, Noémie
Summa1, Isabelle Langlois1,
Jonathan Stockman6 and
Abstract Claire Vergneau Grosset7*
Objective: To describe epidemiological and clinical features of cystine urolithiasis
in pet ferrets.
1
Department of Zoological Medicine,
University of Montreal, Montreal,
Methods: Retrospective case control study on medical records from four private Canada
clinics and one teaching hospital for pet ferrets diagnosed with cystine urolithiasis
2
Division of Veterinary, Community
veterinary Clinic, Longueuil, Canada
confirmed by spectrophotometry presented between July 2014 and July 2019 in 3
Division of Animal Care, Montreal
Quebec, Canada; these cases were then compared to a reference population of Veterinary Hospital for Birds & Exotic
210 ferrets (controls) presented at the same facilities over the same timeframe. Animals, Montreal, Canada
4
Division of Veterinary, Ormière Veterinary
Results: Among the 36 identified cases, most affected ferrets were neutered males Hospital, Quebec, Canada
(32/36, 89%) and the mean age at presentation was 1.8 (± 1.0 standard deviation) 5
Division of Veterinary, Laval Veterinary
year. Grain-free diets of six different brands were offered for at least three weeks Centre, Laval, Canada
prior to the presentation to 34/36 (94%) of the included cases. The ferrets that
6
Department of Clinical Nutrition, College
of Veterinary Medicine & Biomedical
developed cystine urolithiasis were 57.9 times (Odds ratio [OR], 95% Confidence Sciences, Colorado State University,
interval [95% CI]: 11.0, 304.8) more likely to receive a grain-free diet compared to Colorado, Canada
the reference population. No significant difference in the values for the energy, 7
Department of Clinical Sciences, University
protein, cysteine, and methionine contents were detected between the grain- of Montreal, Quebec, Canada
free and the cereal-based diets offered to these pet ferrets. Among ferrets with
uroliths, those with urethral calculi were 4.7 times (OR, 95% CI: 2.1, 10.4) more
likely to develop an acute urinary tract obstruction. *Corresponding author: Grosset CV,
Conclusion: Although a definitive causation could not be drawn solely from these Department of Clinical Sciences, University
clinical cases, this case control study highlights a possible nutritional aetiology in of Montreal, Quebec, Canada
the complex pathogenesis of cystine urolithiasis in ferrets.
Keywords: Cystine; Diet; Ferret, Grain-free; Hematuria; Mustela putorius furo;  claire.grosset@umontreal.ca
Urinary retention; Urolithiasis

Citation: Lamglait B, Brieger A, Rainville

Received: January 11, 2021; Accepted: January 25, 2021; Published: February 01, MP, Maccolini E, Summa N, et al. (2021)
2021 Retrospective Case Control Study of Pet
Ferrets with Cystine Urolithiasis in Quebec,
Canada: Epidemiological and Clinical
Features. J Vet Med Surg Vol.5 No.1: 31.

Introduction Although no cystine urolithiasis was reported in ferrets in the

Cystinuria in humans and dogs is typically characterized by
impaired renal tubular reabsorption of cysteine [1]. Although a
genetic transmission is suggested in studies in humans and dogs,
the aetiology of cystine urolithiasis in ferrets remains unknown
[2,3]. In a retrospective study of cystine urolithiasis, the mean age
at the time of diagnosis in ferrets was approximately four years
[4]. The same authors postulated that an earlier onset of clinical
manifestations would have been expected if a genetic disorder
was the only aetiology. Nevertheless, the prevalence of cystine
uroliths varies depending on the ferret population considered.
United Kingdom, 15% of uroliths were composed of cystine in a
large epidemiological study on North American ferrets from 1981
to 2007 [5,6]. A recent large-scale retrospective study reported
a higher prevalence of cystine urolithiasis in North American
ferrets, which accounted for 93% of the 1014 uroliths submitted
between 2010 and 2018, while this prevalence was 27% among
the uroliths submitted from European ferrets [7]. The aims of the
present case-control study were to describe the epidemiology
and some clinical features of clinical cystine urolithiasis in North
American pet ferrets.

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Materials and Methods with SAS software (SAS Institute, Cary, North Carolina, USA), and
differences were considered significant at p≤0.05.
Case selection
Medical records of domestic ferrets diagnosed with cystine Results
urolithiasis presented between July 2014 and July 2019 from four Epidemiological overview of the control ferrets
private clinics and one teaching hospital were retrospectively
Neutered males represented 112/210 (53.3%) of this population
reviewed. For inclusion, the type of uroliths had to be confirmed
(Table 1). The mean age of admitted ferrets was 3.4 (± 2.1 Standard
by spectrophotometry. Case files were found through a keyword
deviation [SD]) years. The origin was recorded for 151 controls
search within the species “ferret,” using the keywords “cystine”
(72%) and dominated by Marshall Ferrets (149/151, 99%), the
or “urolith”. The following data were deemed critical for inclusion
remaining ferrets being of Canadian origin. The proportion of
and recorded: age at diagnosis, sex, clinical history, diet, clinical
ferrets fed a grain-free diet was 27.6% (58/210, 95% Confidence
signs at presentation, abdominal radiography, location of the
interval [95% CI]: 21.7, 34.2). Among these grain-free diets, 35/58
urolithiasis, therapeutic management and outcome; when
(60%) ferrets were fed diets marketed for ferrets, 22/58 (38%)
available in the medical files, the following data were also
were fed diets marketed for cats. The duration of exposure to the
recorded: origin, duration of exposure to the diet, and other
current diet was recorded for 49 ferrets (23%), and ranged from
diagnostic tests (ultrasonography, urinalysis, urine culture) and
one to 102 months prior to the presentation (median: 57 months,
their results. Cases with missing inclusion criteria were excluded
IQR: 20, 86).
from the study.
Comparison to the control ferret population Variables Cases Controls p value
Age at presentation 1.8 ± 1.0 [0.4; 3.4 ± 2.1 [0.2; <0.0001
The epidemiological characteristics of the reference ferret (years)1 4.3] 10.0]
population were approximated by randomly selecting ferrets Male:female ratio 1:0.12 (32 males, 1:0.86 (113 males, <0.0001
(‘controls’) admitted in the same veterinary facilities over the 4 females) 97 females)
same time period with any reason for presentation, excluding Neutered animals 36/36 (100%) 207/210 (98.6%) 1
confirmed cystine urolithiasis. To be included as controls, the Marshall origin 29/29 (100%) 149/151 (98.7%) 1
following data had to be available in their medical files: date of Grain-free diet 34/36 (94%) 58/210 (27.6%) <0.0001
consultation, age, sex, and diet. These controls were randomly ferret grain-free diet 17/36 (47%) 35/210 (16.7%) 0.001
selected using a random number generator until a control cat grain-free diet 17/36 (47%) 22/210 (10.5%) <0.0001
population of 210 ferrets (five controls per case) was reached. Cereal-based diet 2/36 (6%) 152/210 (72.4%) <0.0001
When available in the medical files, the following data were also ferret cereal-based diet 2/36 (6%) 130/210 (61.9%) <0.0001
recorded: origin, and duration of exposure to the diet. cat cereal-based diet 0/36 (0%) 21/210 (10.0%) <0.0001
Data collected on diets 1
Presented as mean ± standard deviation [minimum; maximum].

The average analysis and the approximate nutrient composition
of the six main diets fed to affected ferrets and the two main
diets fed to ferrets of the reference population were obtained
from the manufacturers. These eight diets represented 94% and
75.7% of the diets distributed to cases and controls, respectively.
Grain-free diets were defined as diets containing no grain
products in the ingredients listed in contrast to cereal-based
diets which contained cereals (mostly wheat and corn). The data
collected were: metabolizable energy, crude protein, cystine, and
methionine concentrations, and the list of ingredients.
Statistics
To compare the epidemiological characteristics of the included
ferrets with cystine urolithiasis and the control population, a t-test
for unequal variances (age; normality checked with Anderson-
Darling test) and chi-square tests (year of consultation, sex, diet)
were used. Multivariable logistic regressions were performed to
establish the odd ratios of having uroliths according to different
independent variables (age, year of consultation, sex, diet), and
to establish the odd ratios of having certain clinical signs (acute
urinary retention, hematuria) as a function of the location of the
uroliths (bladder, urethra). A non-parametric Wilcoxon test was
used to compare the data obtained from the average analysis of
each diet according to its type (cereal-based versus grain-free).
All the descriptive analysis and statistical tests were performed
Table 1: Demographics of and diets fed to ferrets with cystine urolithiasis
(cases) compared with ferrets from the reference population (controls).
Epidemiological overview of the ferrets with cystine urolithiasis
(‘cases’) and comparison to the control population
A total of 36 cases of confirmed cystine urolithiasis met the
inclusion criteria. Thirty-two (89%) were neutered males and
this prevalence was significantly higher compared to the controls
(p<0.0001). The odds of developing cystine urolithiasis increased
by a factor of 8.9 (Odds ratio [OR], 95% CI: 2.5, 31.5) among
neutered males compared to neutered females (p=0.0007) (Table
2). The mean age at diagnosis was 1.8 (± 1.0 SD) year, and ranged
from 5 months to 4.3 years; this was significantly lower than the
age at presentation for the controls (p<0.0001). A grain-free diet
was offered to 34/36 (94%) of the ferrets with cystine urolithiasis
for at least three weeks prior to the presentation. This prevalence
was significantly higher compared to the controls (p<0.0001).
The ferrets that developed cystine urolithiasis were 57.9 (OR,
95% CI: 11.0, 304.8) times more likely to receive a grain-free diet
compared to the controls (p<0.0001). Half of the grain-free diets
fed to affected ferrets were marketed for ferrets, the other half
was marketed for cats. The time to the transition to a grain-free
diet was recorded for seven cases (19%), and ranged from one to
six months prior to the presentation (median: 8 weeks, IQR: 5,

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14). Two ferrets in the same environment presented with cystine of cysteine and methionine on sulfur amino-acids between the
urolithiasis-related urinary signs a few days apart. The odds of grain-free and the cereal-based diets (p>0.11).
having cystine urolithiasis did not vary significantly by year of
Diet Ferrets with cystine Reference ferret
consultation (p=0.290). The origin was recorded for 29 ferrets
urolithiasis population
(80%) with all cases being of Marshall origin; the proportion of
Grain-free diet #11 7/36 (19%) 8/210 (3.8%)
Marshall ferrets in the case and control populations was not
Grain-free diet #22 3/36 (8%) 12/210 (5.7%)
significant different (p=0.335).
Grain-free diet #33 10/36 (28%) 7/210 (3.3%)
Variables Odd ratio (95% p value Grain-free diet #44 6/36 (17%) 6/210 (2.9%)
confidence interval) Grain-free diet #5 5
3/36 (8%) 3/210 (1.4%)
Age at presentation 0.7 (0.5; 1.0) 0.0537 Grain-free diet #66 4/36 (11%) 21/210 (10.0%)
Diet 57.9 (11.0; 304.8) <0.0001 Cereal-based diet #17 0/36 (0%) 51/210 (24.3%)
Sex1 8.9 (2.5; 31.5) 0.0007 Cereal-based diet #28 1/36 (3%) 51/210 (24.3%)
Urolith location 4.7 (2.1; 10.4) 0.0002 1
ZuPreem Grain-free Ferret diet (ZuPreem, Shawnee, Kansas, USA).
1
Conducted only on neutered ferrets (100% of cases, (98.6% of controls). 2
Orijen Cat and Kitten (Champion Petfoods LP, Edmonton, Alberta,
Table 2: Results of the logistic regression analyses evaluating the age at Canada)
presentation, type of diet (grain-free vs. cereal-based), and sex on the
3
Nutrience Grain-free dry food (Rolf C. Hagen Inc., Baie d’Urfé, Quebec,
odds ratio of developing clinical cystine urolithiasis in pet ferrets, and Canada)
the location of urolithiasis (urethra vs. bladder only) on the odds ratio of 4
True North Grain-free diet for ferrets (Rolf C. Hagen Inc., Baie d’Urfé,
presenting a urinary obstruction. Quebec, Canada)
5
Oven-Backed Tradition Grain-free Chicken cat food (Bio Biscuit Inc.,
Analysis of the diets Saint-Hyacinthe, Quebec, Canada)
6
Versele-Laga Complete Ferret (Versele-Laga, Deinze, Belgium)
Different commercial extruded grain-free diets were offered to 7
Totally Ferret Active Show & Pet Formula (Performance Foods Inc.,
the ferrets included in the study (Table 3). The six most commonly Broomfield, Colorado, USA)
fed grain-free diets contained either peas and other legumes (5/6 8
Marshall Premium Ferret (Marshall Pet Products, North Rose, New
diets) and potatoes (5/6 diets); these ingredients were not listed York, USA)
in the two most commonly fed cereal-based diets. The protein
and amino-acid contents of these diets are presented (Table 4) Table 3: Distribution of the main diets fed to ferrets with cystine
urolithiasis (cases) compared with ferrets from the reference population
there was no significant difference in the values for the energy,
(controls).
protein, cysteine, and methionine contents, nor for the ratio

Diet Protein Cysteine Methionine Ratio cysteine/sulfur Ratio methionine/sulfur

(g/1000 kcal) (g/1000 kcal) (g/1000 kcal) amino-acids (%) amino-acid (%)

Grain-free diet #1 88.1 0.95 1.81 34.4 65.6

Grain-free diet #2 106.2 1.04 2.26 31.5 68.5

Grain-free diet #3 95.2 1.14 2 36.4 63.6

Grain-free diet #4 97.7 NA *

NA *
NA *
NA*

Grain-free diet #5 96 1.09 2 35.3 64.7

Grain-free diet #6 92.2 1.22 2.3 34.6 65.4

Cereal-based diet #1 81.1 0.99 2.36 29.5 70.5

Cereal-based diet #2 96.7 1.14 3 27.6 72.4

*
NA not available. The names of the diets are the same as in Table 3.

Table 4: Energy, total protein and sulfur amino acid (cystine, methionine) contents and their proportions of the main grain-free diets fed to domestic
ferrets diagnosed with cystine urolithiasis and cereal-based diets fed to the ferret reference population.

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Journal of Veterinary
Clinical presentation, diagnostic tests and management
Two main clinical presentations were reported in ferrets with
urolithiasis: intermittent hematuria over a few days without
urinary retention (15/36, 42%), or acute urinary retention often
preceded by episodes of dysuria or stranguria (21/36, 58%). In
ferrets with the first clinical presentation, uroliths were only
detected in the urinary bladder, whereas uroliths were visualized
in the urethra of 20/21 (95%) of the ferrets with the latter clinical
presentation. When in the urethra, calculi were always in both
penile and pelvic portions. The odds of developing an acute
urinary retention increased by a factor of 4.7 (95% CI: 2.1, 10.4)
when calculi were present in the urethra compared to in the
bladder only (p=0.0002). The location of the uroliths as reported
in the radiographic reports are summarized (Table 5). When
only present in the bladder, uroliths were single large stones
whereas multiple small uroliths were visible when the urethra
and the ureters were involved. Urine pH measured by dipstick
at presentation (without treatment received) was recorded in 12
cases, and ranged from 5.0 to 7.0 (median of 6.0, Interquartile
Range [IQR]: 6.0, 6.6).
Location of uroliths Proportion
Bladder only 16/36 (44%)
Bladder and urethra* 15/36 (42%)
Urethra* only 3/36 (8%)
Bladder, urethra*, and ureter 2/36 (6%)
*
When in the urethra, calculi were always in both penile and pelvic
portions.
Table 5: Location of the cystine uroliths diagnosed in domestic ferrets as
reported in the radiography reports.
Most of the recorded cases (28/36, 78%) were managed surgically
by cystotomy (26/36, 72%) or by percutaneous cystolithotomy
(PCCL; 3/36, 8%), a minimally invasive calculus retrieval technique
described in pet animals [8]. Post-operative complications led
to the euthanasia of three of the operated individuals. Overall,
euthanasia (at presentation or following surgery) accounted for
the outcome in 10/36 (28%) of the cases. Of note, all the cases
euthanized presented with urethral urolithiasis. Overall, 10/21
(48%) ferrets presented with urethral cystine uroliths were
euthanized. One case was managed medically after urethral
catheterization and supportive care with meloxicam (Metacam;
Boehringer-Ingelheim, Burlington, Ontario); this ferret was also
transitioned to a cereal-based diet and survived for three years
after the initial presentation with the stone still present.
A recurrence of cystine urolithiasis was identified in three cases;
one case, offered a cereal-based diet, developed another episode
nine months after its initial cystotomy. Two other cases, initially
fed a grain-free diet at the time of the first presentation also
presented with a recurrence of cystine urolithiasis respectively
two and seven months after their initial presentation; no diet
transition was performed after their first episodes. No recurrence
was reported in the other ferrets of the case series. Seven ferrets
were radiographed five to eleven months following their initial
presentation; none of them showed recurrence of urolithiasis. All
these seven cases were transitioned to a cereal-based diet after
their initial presentation.
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Discussion
Owing to its reduced solubility in acidic urine, urinary cystine
in high concentrations in affected individuals precipitates to
form crystals and uroliths leading to urinary obstruction [1,2].
Neutered males were overrepresented in the present case
series, accounting for the majority of cases. The same trends
have been reported in a previous study in which male ferrets
accounted for 77% of the affected individuals and appeared to
be 2.5 times more likely to develop cystine uroliths as females
[4,8,9]. As no difference in urine pH was found between males
and females, this sex difference may likely be related to the
anatomy of the urethra of male ferrets that could predispose to
partial or total urethral obstruction [4,9,10]. Male ferrets have a
longer lower urinary tract combined with a tightly angled pelvic
urethral flexure, rigid os penis, and narrow urethral diameter
that may predispose them to urinary blockage [11]. The more
straightforward urethra of female ferrets may allow the passage
of small stones. Hence, some females may remain asymptomatic
while having cystine uroliths in their urinary tract. The mean age
at diagnosis in the present study was 1.8 year with most cases
between one and three years of age. This is younger than the
mean age of 4.1 years reported in the case series of Nwaokorie
and others (2013), however, in the same study, 51% of the cases
occurred between two and four years old. Our data were also
in agreement with a recent study that demonstrated a strong
association between cystine urolithiasis and younger age of the
ferret [7]. In this large-scale retrospective study from 2010 to
2018, two other features were strongly associated with cystine
urolithiasis: North American origin, and later year of submission.
The marked difference in prevalence between populations of
different origins and the increase in prevalence in the last few
years may highlight other contributors to the aetiopathogeny of
this affection, particularly environmental or genetic factors.
The most striking finding of the present case-control study
was a history of consuming a grain-free diet in most affected
cases (94%) whereas only 27.6% of the ferrets in the reference
population were fed grain-free diets. The ferrets that developed
cystine urolithiasis were also 57.9 times more likely to receive
a grain-free diet compared to the reference population. The
popularity of grain-free diets in the pet food industry has
increased in the recent years; the percentage of grain-free cat
food purchases has increased from 4% of total cat food purchases
in 2012 to 9% in 2014, and represented 47% of cat foods in all
channels in 2017 in the USA [12,13]. Similar trends may apply
to ferret food although no published data were available; since
many ferrets are fed cat food (20.5% in the present control
population), they may be more likely to be exposed to grain-
free diets. Some anecdotal correlations between an increased
incidence of cystine urolithiasis in ferret and the introduction
in North America of ferret diets containing legumes, peas and
lentils as alternative carbohydrate sources have been suggested
before [11,14]; this article represents more tangible evidence of
an association between grain-free diets and the development of
cystine urolithiasis in ferrets.
The statistical comparison of the nutrient content of the main
grain-free diets fed to affected ferrets of the present study and the
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main cereal-based diets distributed in the reference population study; cystine calculi were identified in all the ferrets with
did not demonstrate significant differences in the protein and confirmed cystine urolithiasis. Double contrast cystography may
sulfur amino-acid contents. However, legumes and peas are high even be more sensitive in detecting small cystine uroliths than
in plant protein that may alter the urinary environment such as survey radiography [20].
pH or urine concentration. The solubility of cystine in urine is pH-
The outcome of the surgical managements (cystotomy or PCCL) in
dependent; it is relatively insoluble at the usual urine pH range
the present study was fair as survival was recorded in most cases
of 5.5 to 7.5 in dogs [1]. The urine pH can vary according to the
(89%). Overall, euthanasia (at initial presentation or following
diet, and the normal pH in ferrets was reported to be 5.0 to 7.5,
surgery) accounted for 28% of all cases which emphasises the
which is consistent with the results of the ferrets in the present
need for implementation of preventative measures to reduce
study; however, the pH was only available for few affected cases
its incidence. Of importance, intermittent hematuria in ferrets
[10,15]. Future studies should investigate whether the protein
should be addressed early before the condition may evolve into
source may induce changes in the assimilation of these amino-
urinary retention, of most guarded prognosis.
acids, or other factors such as urine pH.
Euthanasia of ferrets presenting with cystine urolithiasis may
Two individuals that did continue to be fed grain-free diets
even be more prevalent as this study included only ferrets with
experienced recurrence of cystine urolithiasis two and seven
confirmed cystine urolithiasis by spectrophotometry; some
months after the initial presentation. In contrast, six of the affected
animals presented with similar clinical signs during the same
ferrets that underwent cystotomy and were then offered cereal-
time period and euthanized because of poor prognosis or
based diets did not show evidence of urolithiasis recurrence on
financial restrictions were not included because the presence
radiographs taken five to 11 months after the surgery. However,
and composition of uroliths were not confirmed (at least 25
not all ferrets fed a grain-free diet develop a cystine urolithiasis
euthanized ferrets fed grain-free diets were excluded as the type
and two affected ferrets in the present study were fed cereal-
of uroliths was not confirmed).
based diets. Moreover, only some individuals were reported to
develop cystine urolithiasis in several multi-ferret households As a retrospective case-control study, this paper presents some
that fed all ferrets exclusively grain-free diets [11]. limitations and biases that may influence its conclusions or
reduce its relevance. Firstly, some data recorded in the medical
A possible nutritional origin does not exclude a genetic basis that
files were missing, which led to the exclusion of some records;
may predispose some lineages to produce this type of urolith;
the medical files analysed were also from different veterinary
evidence of little genetic variability among most pet ferrets in
clinics with differences in medical data recording. This study
North America may support a familial predisposition for this
highlights a possible association between grain-free diets and
disease [16]. In humans, dogs and cats, cystinuria is an inherited
the development of cystine urolithiasis in ferrets; nevertheless,
metabolic defect of amino-acid transport causing a failure in
the duration of exposure to a grain-free diet was occasionally
reabsorption of filtered cystine in the proximal tubule [1,2], and has
recorded in the medical files, and further work will be needed to
been documented to be caused by mutations in either the SLC3A1
assess this association.
or SLC7A9 genes [3,17-19]. Excessive inbreeding of domesticated
ferrets in North America could have contributed to an increase in
the prevalence of one or more mutations contributing to faulty Conclusion
amino acid reabsorption in the proximal tubules. This genetic
This case series allowed to evaluate new elements in the
predisposition may also be supported by the two ferrets of the
epidemiology of cystine urolithiasis that showed a marked
present series that developed cystine urolithiasis but were never
increase in incidence in pet ferrets in the last decade. As
fed grain-free diets. A complex aetiopathogenesis involving
already mentioned in several studies, male ferrets and young
genetic and environmental components in the development of
individuals were overrepresented; a strong association with
cystine urolithiasis in pet ferrets may also be emphasised by the
grain-free diets was shown, without causation being established.
low prevalence of this condition in the United Kingdom, where
This study therefore reinforced the possibility of a complex
ferrets more commonly are fed whole-prey or legume-free diets
aetiopathogenesis of cystine urolithiasis in ferrets for which
[5,11]. The impact of the origin of the ferrets included in the
genetic and environmental factors (including diet) are probably
present study could not be evaluated as all animals were of North
involved. Future studies are needed to assess possible genetic
American origin, and most of them of Marshall origin.
mutations, as in humans or other domestic carnivores, or changes
The present study highlights two main clinical presentations linked in urinary environment and amino-aciduria in affected ferrets.
to the location of the calculi: most cases with identified calculi in
the urethra presented with urinary retention, often preceded by References
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